A distinguished flu vaccine researcher

Congratulations to Richard Compans, PhD, who discussed his flu vaccine research in the Dean's Distinguished Faculty Read more

Fooling the test: antibiotic resistant bacteria that look susceptible

The phenomenon of heteroresistance could be causing unexplained treatment failures in the clinic and highlights the need for more sensitive diagnostic tests. Enterobacter cloacae from CDC image Read more

Optic nerve reaching out

Contest-winning image of optic nerve axon from Emory Eye Read more

Cancer

Three-stage delivery for platinum-based “cluster bombs” against cancer

Scientists have devised a triple-stage “cluster bomb” system for delivering the chemotherapy drug cisplatin, via tiny nanoparticles designed to break up when they reach a tumor.

Details of the particles’ design and their potency against cancer in mice are described this week in PNAS Early Edition. They have not been tested in humans, although similar ways of packaging cisplatin have been in clinical trials. Anticancer cluster bombs

What makes these particles distinctive is that they start out relatively large — 100 nanometers wide – to enable smooth transport into the tumor through leaky blood vessels. Then, in acidic conditions found close to tumors, the particles discharge “bomblets” just 5 nanometers in size.

Inside tumor cells, a second chemical step activates the platinum-based cisplatin, which kills by crosslinking and damaging DNA. Doctors have used cisplatin to fight several types of cancer for decades, but toxic side effects – to the kidneys, nerves and inner ear — can limit its effectiveness.

The PNAS paper is the result of a collaboration between a team led by professor Jun Wang, PhD at the University of Science and Technology of China, and researchers led by professor Shuming Nie, PhD in the Wallace H. Coulter Department of Biomedical Engineering at Georgia Tech and Emory. Nie is a member of the Discovery and Developmental Therapeutics research program at Winship Cancer Institute of Emory University. The lead authors are graduate student Hong-Jun Li and postdoctoral fellows Jinzhi Du, PhD and Xiao-Jiao Du, PhD.

“The negative side effects of cisplatin are a long-standing limitation for conventional chemotherapy,” says Jinzhi Du. “In our study, the delivery system was able to improve tumor penetration to reach more cancer cells, as well as release the drugs specifically inside cancer cells through their size-transition property.”

The researchers showed that their nanoparticles could enhance cisplatin drug accumulation in tumor tissues. When mice bearing human pancreatic tumors were given the same doses of free cisplatin or cisplatin clothed in pH-sensitive nanoparticles, the level of platinum in tumor tissues was seven times higher with the nanoparticles. This suggests the possibility that nanoparticle delivery could restrain the toxic side effects of cisplatin during cancer treatment. Read more

Posted on by Quinn Eastman in Cancer Leave a comment

Lung cancer cells go amoeboid

Cancer biologists Jessica Konen and Scott Wilkinson, in Adam Marcus’ lab, recently published a paper on the function of LKB1, a gene that is often mutated in lung cancer cells. [Number three behind K-ras and p53.]

Amoeboid

Mesenchymal shape is defined as having a length more than twice the width. Amoeboid looks more like the cell on the right: rounded up. Thanks to Jessica Konen for photo.

Konen and Marcus were featured in a prize-winning video that our team produced last year, which discusses how they developed a technique for isolating “leader cells” — lung cancer cells that migrate and invade more quickly — from a large group and studying those cells’ properties more intensively.

The Molecular Biology of the Cell paper covers a related topic: how LKB1 mutation affects cell shape. In particular, losing LKB1 converts lung cancer cells from a “mesenchymal” morphology to an “amoeboid” morphology.  Read more

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Device for viewing glowing brain tumors

People touched by a brain tumor — patients, their families or friends — may have heard of the drug Gliolan or 5-ALA, which is taken up preferentially by tumor cells and makes them fluorescent. The idea behind it is straightforward: if the neurosurgeon can see the tumor’s boundaries better during surgery, he or she can excise it more thoroughly and accurately.

5-ALA is approved for use in Europe but is still undergoing evaluation by the U.S. FDA. A team at Emory was the first to test this drug in the United States. [Note: A similar approach, based on protease activation of a fluorescent probe, was reported last week in Science Translational Medicine.]

ac-2015-034535_0001

A hand-held device to detect glowing brain tumors could allow closer access to the critical area than a surgical microscope

Biomedical engineer Shuming Nie and colleagues recently described their development of a hand-held spectroscopic device for viewing fluorescent brain tumors. This presents a contrast with the current tool, a surgical microscope — see figure.

Nie’s team tested their technology on specimens obtained from cancer surgeries. Their paper in Analytical Chemistry reports:

The results indicate that intraoperative spectroscopy is at least 3 orders of magnitude more sensitive than the current surgical microscopes, allowing ultrasensitive detection of as few as 1000 tumor cells. Read more

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Chasing invasive cancer cells and more at #ASCB15

Earlier today, we posted a notice on Eurekalert for a Sunday, December 13 presentation by graduate student Jessica Konen at the American Society for Cell Biology meeting in San Diego.

Her research, performed with Adam Marcus at Winship Cancer Institute, was the topic of a video that recently won first prize in a contest sponsored by the Association of American Medical Colleges. This was our video team’s first use of the “fast hand on whiteboard” effect, and a lot of fun to make. The video’s strength grows out of the footage Konen and Marcus have of cancer cells migrating in culture. Check it out, if you haven’t already.

Poster presentations at the 2015 ASCB meeting can be found by searching this PDF. A few Emory-centric highlights:

*Chelsey Ruppersburg and Criss Hartzell’s work on the “nimbus”, a torus-shaped structure enriched in proteins needed to build the cell’s primary cilium

*Anita Corbett on how Emory students have a strong record of attaining their own NIH research funding

*Additional work by Adam Marcus’ lab on the tumor suppressor gene LKB1 and how its loss drives lung cancer cells to take on a “unique amoeboid morphology”

*Research from David Katz’s lab on the “epigenetic eraser” LSD1 (lysine-specific demethylase) and its function in neurons and neurodegeneration Read more

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Graft vs host? Target the aurora

 

Graft-vs-host disease is a common and potentially deadly complication following bone marrow transplants, in which immune cells from the donated bone marrow attack the recipient’s body.

Winship Cancer Institute’s Ned Waller and researchers from Children’s Healthcare of Atlanta and Yerkes National Primate Research Center were part of a recent Science Translational Medicine paper that draws a bright red circle around aurora kinase A as a likely drug target in graft-vs-host disease.

Aurora kinases are enzymes that control mitosis, the process of cell division, and were first discovered in the 1990s in yeast, flies and frogs. Now drugs that inhibit aurora kinase A are in clinical trials for several types of cancer, and clinicans are planning to examine whether the same type of drugs could help with graft-vs-host disease.

Leslie Kean, a pediatric cancer specialist at Seattle Children’s who was at Emory until 2013, is the senior author of the STM paper. Seattle Childrens’ press release says that Kean wears a bracelet around her badge from a pediatric patient cured of leukemia one year ago, but who is still in the hospital due to complications from graft-vs-host. Read more

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Anticancer drug strategy: making cells choke on copper

What do cancer cells have in common with horseshoe crabs and Mr. Spock from Star Trek?

They all depend upon copper. Horseshoe crabs have blue blood because they use copper to transport oxygen in their blood instead of iron (hemocyanin vs hemoglobin). Vulcans’ blood was supposed to be green, for the same reason.

Horseshoe Crab (Limulus polyphemus)

Horseshoe crabs and Vulcans use copper to transport oxygen in their blood. Cancer cells seem to need the metal more than other cells.

To be sure, all our cells need copper. Many human enzymes use the metal to catalyze important reactions, but cancer cells seem to need it more than healthy cells. Manipulating the body’s flow of copper is emerging as an anticancer drug strategy.

A team of scientists from University of Chicago, Emory and Shanghai have developed compounds that interfere with copper transport inside cells. These compounds inhibit the growth of several types of cancer cells, with minimal effects on the growth of non-cancerous cells, the researchers report in Nature Chemistry.

“We’re taking a tactic that’s different from other approaches. These compounds actually cause copper to accumulate inside cells,” says co-senior author Jing Chen, PhD, professor of hematology and medical oncology at Emory University School of Medicine and Winship Cancer Institute. Read more

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Orange lichens are source for potential anticancer drug

An orange pigment found in lichens and rhubarb called parietin may have potential as an anti-cancer drug, scientists at Winship Cancer Institute of Emory University have discovered.

The results were published in Nature Cell Biology on October 19.

Caloplaca_Fenwick

Parietin, shown to have anticancer activity in the laboratory, is a dominant pigment in Caloplaca lichens. Note: this study did not assess the effects of eating lichens or rhubarb. Photo courtesy of www.aphotofungi.com

Parietin, also known as physcion, could slow the growth of and kill human leukemia cells obtained directly from patients, without obvious toxicity to human blood cells, the authors report. The pigment could also inhibit the growth of human cancer cell lines, derived from lung and head and neck tumors, when grafted into mice.

A team of researchers led by Jing Chen, PhD, discovered the properties of parietin because they were looking for inhibitors for the metabolic enzyme 6PGD (6-phosphogluconate dehydrogenase). 6PGD is part of the pentose phosphate pathway, which supplies cellular building blocks for rapid growth. Researchers have already found 6PGD enzyme activity increased in several types of cancer cells.

“This is part of the Warburg effect, the distortion of cancer cells’ metabolism,” says Chen, professor of hematology and medical oncology at Emory University School of Medicine and Winship Cancer Institute. “We found that 6PGD is an important metabolic branch point in several types of cancer cells.” Read more

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Cancer metastasis: isolating invasive cells with a color change

The capacity of cancer cells to spread throughout the body and invade new tissues – to become metastatic — makes them deadly. What makes metastatic cells different? Scientists at Winship Cancer Institute of Emory University have developed a technique for isolating individual cells that display invasive behavior out of a large group in culture by changing their color.

Read more

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SUMO wrestling enzyme important in DNA repair

The DNA in our cells is constantly being damaged by heat, radiation and other environmental stresses, and the enzyme systems that repair DNA are critical for life. A particularly toxic form of damage is the covalent attachment of a protein to DNA, which can be triggered by radiation or by anticancer drugs.

Keith Wilkinson, PhD

Emory biochemist Keith Wilkinson and colleagues have a paper this week in the journal eLife probing how a yeast protein called Wss1 is involved in repairing DNA-protein crosslinks. The researchers show how Wss1 wrestles with a protein tag called SUMO on the site of the DNA damage, and how Wss1 and SUMO are involved in the cleanup process.

Three interesting things about this paper:

*The paper grew out of first author Maxim Balakirev’s sabbatical with Wilkinson at Emory. Balakirev’s home base is at the CEA (Alternative Energy and Atomic Energy Commission) in Grenoble, France.

* Since many cancer chemotherapy drugs induce protein-DNA cross links, an inhibitor of cross link repair could enhance those drugs’ effectiveness. On the other side of the coin, mutations in a human gene called Spartan, whose sequence looks similar to Wss1’s, cause premature aging and susceptibility to liver cancer. Whether the Spartan-encoded protein has the same biochemical activity as Wss1 is not yet clear.

*SUMO stands for “small ubiquitin-like modifier”. The eLife digest has an elegant explanation of what’s happening: Read more

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Adaptive mutation mechanism may drive some forms of antibiotic resistance

Evolutionary theory says mutations are blind and occur randomly. But in the controversial phenomenon of adaptive mutation, cells can peek under the blindfold, increasing their mutation rate in response to stress.

Scientists at Winship Cancer Institute, Emory University have observed that an apparent “back channel” for genetic information called retromutagenesis can encourage adaptive mutation to take place in bacteria.

The results were published Tuesday, August 25 in PLOS Genetics.

“This mechanism may explain how bacteria develop resistance to some types of antibiotics under selective pressure, as well as how mutations in cancer cells enable their growth or resistance to chemotherapy drugs,” says senior author Paul Doetsch, PhD.

Doetsch is professor of biochemistry, radiation oncology and hematology and medical oncology at Emory University School of Medicine and associate director of basic research at Winship Cancer Institute. The first author of the paper is Genetics and Molecular Biology graduate student Jordan Morreall, PhD, who defended his thesis in April.

Retromutagenesis resolves the puzzle: if cells aren’t growing because they’re under stress, which means their DNA isn’t being copied, how do the new mutants appear?

The answer: a mutation appears in the RNA first. Read more

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